Lipids Contribute to Heterochromatin Condensation Revealed by Quantitative Raman-Brillouin Microscopy

Chromatin is a dynamic, higher-order structure that compacts genomic DNA within the nucleus and regulates genome organization and accessibility. Chromatin is broadly classified into transcriptionally inert heterochromatin and active euchromatin based on their condensation states; however, the molecular basis underlying this condensation difference remains unresolved. In this study, we show that phosphatidylcholine-type lipid molecules are associated with heterochromatin in living cells and contribute to its physical condensation. Using label-free Raman-Brillouin microscopy, we simultaneously mapped molecular concentrations and high-frequency viscoelastic properties in a living cell at subcellular resolution. Raman imaging revealed that lipid molecules are selectively enriched in heterochromatin, and their local concentrations are correlated with the mechanical response of heterochromatin. These lipids were absent from mitotic chromosomes and reappeared in DNA-rich regions during the early G1 phase, indicating that lipid incorporation is a regulated step in the formation of heterochromatin. These results expand the molecular view of chromatin and demonstrate how simultaneous Raman-Brillouin imaging can link chemical constituents with the mechanical properties of a cell.